U.S. patent application number 14/336076 was filed with the patent office on 2014-11-06 for catheter for performing photodynamic ablation of cardiac muscle tissue via photochemical reaction.
The applicant listed for this patent is KEIO UNIVERSITY. Invention is credited to Tsunenori Arai, Arisa Ito.
Application Number | 20140330261 14/336076 |
Document ID | / |
Family ID | 44507022 |
Filed Date | 2014-11-06 |
United States Patent
Application |
20140330261 |
Kind Code |
A1 |
Arai; Tsunenori ; et
al. |
November 6, 2014 |
CATHETER FOR PERFORMING PHOTODYNAMIC ABLATION OF CARDIAC MUSCLE
TISSUE VIA PHOTOCHEMICAL REACTION
Abstract
This invention provides a catheter used for blocking abnormal
conduction in the cardiac muscle using photodynamic therapy or
treating arrhythmia and a method for evaluating the therapeutic
effects of the catheter. The catheter has a structure that freely
bends at its end, which is used for performing photodynamic
ablation of cardiac muscle tissue via photochemical reactions in
the blood vessel or cardiac lumen. The catheter comprises a
light-emitting window for applying a light beam transmitted through
an optical fiber to a target site of cardiac muscle tissue and at
least two electrodes for potential measurement in the periphery of
the light-emitting window.
Inventors: |
Arai; Tsunenori; (Kanagawa,
JP) ; Ito; Arisa; (Kanagawa, JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
KEIO UNIVERSITY |
Tokyo |
|
JP |
|
|
Family ID: |
44507022 |
Appl. No.: |
14/336076 |
Filed: |
July 21, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13581105 |
Aug 24, 2012 |
|
|
|
PCT/JP2011/055004 |
Feb 25, 2011 |
|
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14336076 |
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Current U.S.
Class: |
606/15 |
Current CPC
Class: |
A61B 18/24 20130101;
A61N 5/062 20130101; A61B 2018/00577 20130101; A61B 2018/00839
20130101; A61B 2018/00351 20130101; A61N 5/0603 20130101; A61N
5/0601 20130101 |
Class at
Publication: |
606/15 |
International
Class: |
A61B 18/24 20060101
A61B018/24 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 26, 2010 |
JP |
2010-042669 |
Claims
1. A method for performing photodynamic ablation of cardiac muscle
tissue via photochemical reactions in blood vessel or cardiac lumen
and evaluating photodynamic ablation effects using a catheter
comprising a light-emitting window for irradiating a target site of
cardiac muscle tissue with a light beam transmitted through an
optical fiber and two electrodes A and B for potential measurement
located in the periphery of the light-emitting window so as to
sandwich the same, the method comprising, (i) irradiating cardiac
muscle tissue with the light beam emitted from the light-emitting
window to ablate the tissue, and (ii) measuring potential
differences at sites on both sides of the cardiac muscle tissue
subjected to ablation by measuring potential firstly with electrode
A and them with B, wherein a temporal delay in the electric
potential waveform at electrode B indicates disappearance of
electric conductivity in a region between two electrodes A and B
due to the photodynamic ablation of the tissue, and no detection of
electrical signals at electrode B indicates the loss of electric
conductivity across all the cardiac muscle tissue wall layer due to
the photodynamic ablation of the tissue.
2. The method according to claim 1, wherein the catheter has an end
that freely bends.
3. The method according to any one of claim 1, wherein the catheter
emits light in the lateral direction, and comprises the
light-emitting window and two electrodes A and B for potential
measurement in the periphery of the window in a manner such that
the first electrode A for potential measurement, a light-emitting
window capable of emitting light laterally from the catheter, and
the second electrode B for potential measurement are arranged
sequentially in that order from the catheter end.
4. The method according to claim 3, wherein the first electrode A
of the catheter for potential measurement has a dome shape and the
second electrode B of the catheter for potential measurement has a
ring shape.
5. The method according to claim 3, wherein the light-emitting
window of the catheter has a ring or cylinder shape.
6. The method according to claim 3, wherein the catheter comprises
a single or a plurality of construct(s) for allowing a light beam
to reflect in an arbitrary direction inside itself, so that the
light beam transmitted through an optical fiber is reflected in a
lateral direction.
7. The method according to claim 6, wherein the construct that
allows a light beam to reflect in an arbitrary direction is a
mirror, prism, or lens or a combination of two or more thereof
8. The method according to claim 1, wherein the light-emitting
window having cylindrical shape with a spherical end of the
catheter is provided at a catheter end, the light beam transmitted
through an optical fiber is emitted from the light-emitting window
coaxially with a long axis of the catheter, two planar electrodes A
and B in the form of curved plane for potential measurement are
provided in the periphery of the light-emitting window of the
catheter.
9. The method according to claim 1, wherein the catheter further
comprises at least one marker for monitoring the direction of an
emitted light beam from outside of a body in the vicinity of the
distal end of the catheter, and the position or configuration of
the marker is associated with the direction of the irradiation of a
light beam from the catheter.
10. The method according to claim 9, wherein markers are provided
asymmetrically relative to a long axis of the catheter.
11. The method according to claim 9, wherein the marker for
monitoring the direction of an emitted light beam from outside of a
body is in the form of a line, ribbon, or ring and it is provided
so as to cross a long axis of the catheter along the outer
periphery of the distal end of the catheter.
12. The method according to claim 9, wherein the marker for
monitoring the direction of an emitted light beam from outside of a
body is a radiopaque marker.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a Divisional of U.S. application Ser.
No. 13/581,105, which is the U.S. National Stage application of
PCT/JP2011/055004, filed Feb. 25, 2011, which claims priority from
Japanese application JP 2010-042669, filed Feb. 26, 2010.
TECHNICAL FIELD
[0002] The present invention relates to the field of treatment and
photodynamic therapy for arrhythmia, such as atrial fibrillation,
caused as a result of abnormal cellular electrical conduction or
hyperexcitability. The present invention also relates to a catheter
that performs photodynamic ablation of cardiac muscle tissue via
photochemical reaction.
BACKGROUND ART
[0003] Radio frequency ablation, cryoablation, laser ablation, and
the like are currently available means for blocking electric
conduction of cardiac muscle tissue, and such means thermally
damage tissue, so as to block electric conduction. Such techniques
are employed as means for treating irregular heartbeat caused by
abnormal electrical signals, which is known as cardiac
arrhythmia.
[0004] Tachyarrhythmia is a type of arrhythmia that conducts
hyperexcitability to normal cardiac muscle tissue or forms an
electric excitation reentry circuit in cardiac muscle tissue. In
general, cardiac excitation is controlled at a normal rate (i.e.,
the sinus rhythm) through excitation caused by the sinoatrial node.
In the case of tachyarrhythmia, however, the heartbeat is
maintained at a faster rate than the sinus rhythm due to
hyperexcitability that takes place in part of the cardiac tissue.
The term "reentry circuit" refers to a region where normal electric
excitation is not conducted but circles because of the presence of
a site of impaired conduction in cardiac muscle tissue. The reentry
circuit is associated with persistence of tachyarrhythmia, and
development and conduction of hyperexcitability cause
tachyarrhythmia attacks. For example, atrioventricular nodal
reentry tachycardia (AVNRT) attacks are caused by premature atrial
contraction, and such arrhythmia is maintained due to the formation
of a reentry circuit in the atrioventricular node and part of the
atrium. In such a case, part of the reentry circuit may be blocked
by catheter ablation or other means as a radical treatment. In
addition, an example of tachyarrhythmia cause of attack of which
has been found to exist at a specific site and for which radical
treatment is provided for preventing attack includes atrial
fibrillation (AF).
[0005] For example, atrial fibrillation (AF) is a type of cardiac
arrhythmia that is caused by irregular atrial excitation, and such
arrhythmia causes thrombotic obstruction, such as cerebral
infarction. Paroxysmal atrial fibrillation is caused by an
aberration in electrical signals from the left atrium (LA) to the
pulmonary vein (PV) in cardiac muscle tissue. When atrial
fibrillation occurs, the atrioventricular node receives electrical
impulses from many sites from the entire atrium, in addition to the
sinoatrial node. The atrioventricular node cannot completely
process such impulses and, as a consequence, generates irregular,
rapid heartbeats. As a result, the blood remains in the atrium, and
it increases the risk of the formation of blood clots. Examples of
major atrial fibrillation risk factors include age, coronary
disease, rheumatic heart disease, elevated blood pressure,
diabetes, and thyrotoxicosis.
[0006] A large number of patients with arrhythmia have atrial
fibrillation, and such patients account for approximately one-third
of all arrhythmia patients. At present, the number of patients is
deduced to be approximately 0.73 million, and such number is likely
to increase with aging. While 1% or less of the entire population
has atrial fibrillation at age 60 or younger, several percent of
the population aged in their 60s, 5% in their 70s, and 10% or more
in their 80s have atrial fibrillation. Drug therapy is conservative
therapy that cannot radically cure the disease, and drug therapy is
often ineffective in the case of chronic atrial fibrillation.
Atrial fibrillation progresses from paroxysmal fibrillation to
chronic atrial fibrillation with the elapse of time, and it becomes
a major risk factor causing cardiac failure, cerebral infarction,
and the like.
[0007] As a radical alternative treatment to drug therapy, catheter
ablation is available (see JP Patent Publication (Kokai) No.
2004-130095 A, Carlo Pappone et al., Circulation, 2000; 102;
2619-2628, Mathaniel M. Fried et al., Lasers in Surgery and
Medicine 28: 197-203, 2001, Kazushi Tanaka et al., Journal of
American College of Cardiology, Vol. 38, No. 7, December 2001,
2079-2086, and Walid Saliba et al., Journal of Cardiovascular
Electrophysiology, Volume 13, No. 10, October 2002, 957-961).
According to the guidelines issued by academic societies in Europe
and U.S.A. (ACC/AHA/ESC) in 2008, catheter ablation of atrial
fibrillation was officially announced as the second-line therapy,
following drug therapy. The current radio frequency catheter
ablation comprises pin-point cauterization, with an electrode at
the end. When pulmonary vein isolation is performed, it is
necessary to deliver radio frequency current many times in order to
form a continuous ablation line surrounding the pulmonary vein. It
is difficult to form a completely continuous ablation line, and
gaps cause reconductance. In addition, it is difficult to control
the intratissue temperature with such technique, the temperature
within the intramyocardial depth becomes higher than the
temperature that is actually set, which causes popping phenomena,
and embolism may be induced by char (blood clot) resulting
therefrom. Since the temperature in tissue cannot be determined,
the ablation depth cannot be controlled, and serious complications
such as esophageal perforation and diaphragmatic disorders have
been reported.
[0008] Accordingly, development of transmural therapeutic
techniques that impart little damage to the atrial tissue and
tissues in the vicinity thereof and control thermal damage imparted
to the atrial tissue has been desired.
[0009] In general, photodynamic therapy is employed for cancer
treatment or other purposes. Application of photodynamic therapy
(PDT; also referred to as "photochemical therapy") to various types
of therapy, in addition to endoscopic therapy for early-stage
cancer, has been examined (see JP Patent No. 2,961,074, JP Patent
Publication (JP Patent Publication (Kokoku) No. H07-53733 B (1995)
and the like). photodynamic therapy is a therapeutic technique
comprising administering an agent for photodynamic therapy such as
a certain type of porphyrin derivative via intravenous injection or
other means, allowing the agent for photodynamic therapy to be
selectively absorbed and to accumulate at a tissue site at which a
lesion such as cancer tissue to be treated is observed, and be
irradiated with a ray such as a laser beam to destroy such tissue.
This technique makes use of properties of an agent for photodynamic
therapy being selectively accumulated in a lesion and being
sensitized by light. At present, however, some therapeutic
techniques do not involve the use of accumulating properties. This
technique is based on a mechanism that an agent for photodynamic
therapy integrated into a lesion is excited by light irradiation,
energy of the sensitizer is transferred to oxygen that is present
in the lesion to generate active, singlet oxygen, and such active
oxygen causes cell apoptosis or necrosis in the lesion.
[0010] A method for treatment of arrhythmia by photodynamic therapy
involving the use of a fat-soluble porphyrin agent for photodynamic
therapy and a balloon catheter has been reported (US Patent
Application S2002/0095197), although specific conditions and the
like of the therapy have not been reported.
[0011] Therefore, a transmural treatment method that causes minimal
damage to atrial tissues and tissues surrounding the same and
prevents thermal damage to atrial tissues has been desired.
[0012] An apparatus that performs ablation of cardiac muscle tissue
to treat arrhythmia using photodynamic therapy had been reported
(WO 2008/066206). Cardiac muscle tissue ablation using photodynamic
therapy is not carried out thermally. Active oxygen (singlet
oxygen) generated via photochemical reactions among 3 elements
(i.e., an agent for photodynamic therapy light, and oxygen) damages
cells to cause necrosis in cardiac muscle tissue, and this involves
the use of an optical catheter that can be freely operated in the
body. It can be said that such technique is substantially free of
the risk of causing complications resulting from difficulties in
temperature control, which is a problem for catheter ablation at
present. However, no satisfactory therapeutic effects could be
observed using such apparatus.
SUMMARY OF THE INVENTION
[0013] An object of the present invention is to provide a catheter
and a method for the treatment of arrhythmia by blocking abnormal
conduction in the cardiac muscle by photodynamic therapy, the
therapeutic effects of which can be evaluated.
[0014] The present inventors discovered that a target region could
be subjected to ablation precisely by photodynamic therapy while
using light for irradiation without damaging tissue surrounding the
target region. They also discovered that administration of an agent
for photodynamic therapy via intravenous injection or other means
would lead to distribution of the agent for photodynamic therapy
outside cells at the treatment site within a short period of time
after administration of the agent for photodynamic therapy, so that
treatment could be initiated without waiting for a long time after
administration. Thus, they developed an apparatus for photodynamic
therapy (International Publication No. WO 2008/066206). The present
inventors refer to "ablation by photodynamic therapy" as
"photodynamic ablation."
[0015] Further, the present inventors discovered that the
occurrence or duration of transmission of electric potential
between two points may be measured in order to confirm that
photodynamic ablation was adequately performed and the target site
in cardiac muscle tissue was necrotized. The present inventors
discovered that at least two electrodes for electric potential
measurement may be provided in the periphery of the light-emitting
window for emitting the light beam from a catheter that performs
photodynamic ablation, so that the differences in electrical
potential between two points sandwiching the target site in cardiac
muscle tissue can be measured, whether or not electricity is
transmitted to the target site can be determined, and whether or
not the target site is necrotized by photodynamic ablation can be
determined in the end. This has led to the completion of the
present invention.
[0016] Specifically, the present invention is as follows.
[0017] [1] A catheter used for performing photodynamic ablation of
cardiac muscle tissue via photochemical reactions in the blood
vessel or cardiac lumen, the catheter comprising a light-emitting
window for irradiating the target site of cardiac muscle tissue
with a light beam transmitted through an optical fiber and at least
two electrodes for potential measurement in the periphery of the
light-emitting window.
[0018] [2] The catheter according to [1], which has an end that
freely bends.
[0019] [3] The catheter according to [1] or [2], wherein two
electrodes for potential measurement are provided in the periphery
of the light-emitting window so as to sandwich the window.
[0020] [4] The catheter according to any of [1] to [3], which emits
light in the lateral direction, and comprises the light-emitting
window and at least two electrodes for potential measurement in the
periphery of the window in a manner such that the first electrode
for potential measurement, a light-emitting window capable of
emitting light laterally from the catheter, and the second
electrode for potential measurement are arranged sequentially in
that order from the catheter end.
[0021] [5] The catheter according to [4], wherein the first
electrode for potential measurement has a dome shape and the second
electrode for potential measurement has a ring shape.
[0022] [6] The catheter according to [4] or [5], wherein the
light-emitting window has a ring or cylinder shape.
[0023] [7] The catheter according to any of [4] to [6], which
comprises a single or a plurality of construct(s) for allowing a
light beam to reflect in an arbitrary direction inside itself, so
that the light beam transmitted through an optical fiber is
reflected in a lateral direction.
[0024] [8] The catheter according to [7], wherein the construct
that allows a light beam to reflect in an arbitrary direction is a
mirror, prism, or lens or a combination of two or more thereof.
[0025] [9] The catheter according to any of [1] to [3], wherein a
cylindrical light-emitting window with a spherical end is provided
at a catheter end, a light beam transmitted through an optical
fiber is emitted from the light-emitting window coaxially with a
long axis of the catheter, at least two planar electrodes for
potential measurement are provided in the periphery of the
light-emitting window, and a light beam is emitted coaxially with a
long axis of the catheter.
[0026] [10] The catheter according to any of [1] to [9], which
further comprises at least one marker for monitoring the direction
of an emitted light beam from outside of a body in the vicinity of
the distal end of the catheter, and the position or configuration
of the marker is associated with the direction of the irradiation
of a light beam from the catheter.
[0027] [11] The catheter according to [10], wherein markers are
provided asymmetrically relative to a long axis of the
catheter.
[0028] [12] The catheter according to [10] or [11], wherein the
marker for monitoring the direction of an emitted light beam from
outside of a body is in the form of a line, ribbon, or ring and it
is provided so as to cross a long axis of the catheter along the
outer periphery of the distal end of the catheter.
[0029] [13] The catheter according to any of [10] to [12], wherein
the marker for monitoring the direction of an emitted light beam
from outside of a body is a radiopaque marker.
[0030] [14] The catheter according to any of [10] to [13], wherein
the marker for monitoring the direction of an emitted light beam
from outside of a body also serves as an electrode for potential
measurement.
[0031] [15] The catheter according to any of [10] to [14], wherein
the light beam is a laser or LED light.
[0032] [16] A photodynamic ablation catheter apparatus which blocks
abnormal electrical conduction of the cardiac muscle by conducting
photodynamic therapy using an agent for photodynamic therapy and a
light beam at the excitation wavelength of the agent for
photodynamic therapy,
[0033] the apparatus comprising the catheter according to any of
[1] to [15], a means for generating a light beam with which an
abnormal electrical conduction site or hyperexcitability site is
irradiated, and a means for transmitting the light beam to the
abnormal electrical conduction site.
[0034] When a therapeutic apparatus utilizing the photodynamic
therapy according to the present invention is used, the abnormal
electrical conduction site or hyperexcitability site of the cardiac
muscle is subjected to photodynamic ablation via photochemical
reactions that necrotize tissue cells with active oxygen instead of
heat, so as to block the abnormal conduction site of the cardiac
muscle. Accordingly, damages imposed on cardiac muscle tissue and
tissue in the vicinity thereof can be small. When such technique is
used in the vicinity of the pulmonary vein for the purpose of
treatment of atrial fibrillation, side effects such as coarctation
resulting from destruction of peripheral tissue by heat can be
reduced. In particular, targets of the apparatus of the present
invention are subjects who have taken the agents for photodynamic
therapy. Since the agent for photodynamic therapy is distributed in
the extracellular matrix of the myocardial treatment site shortly
after administration of the agent for photodynamic therapy,
treatment can be initiated shortly after administration of the
agent for photodynamic therapy. According to conventional radio
frequency catheter ablation techniques for treatment of arrhythmia,
it has been impossible to selectively treat the target sites. This
is because the target sites are subjected to ablation with heat,
and normal tissue in the vicinity of the target sites would be
subjected to ablation due to heat conduction. The apparatus of the
present invention, however, does not involve the use of heat that
can be conducted, and the apparatus implements photodynamic
ablation via photochemical reactions involving the use of a light
beam capable of limiting the relevant area. This enables limitation
of treatment sites. When the apparatus is used for treatment of
atrial fibrillation, for example, side effects such as perforation
of peripheral tissues (e.g., the esophagus) can be reduced. Pain
resulting from fever can also be avoided. In addition, photodynamic
ablation can be performed more continuously than is possible with
ablation with heat. This can shorten an operation duration.
[0035] Further, provision of at least two electrodes for potential
measurement in the periphery of the window that emits a light beam
enables determination regarding whether or not cardiac muscle
tissue cells have been led to necrosis by photodynamic ablation at
the target site irradiated with a light beam. This enables
evaluation of the effects of photodynamic ablation via
photochemical reactions using a catheter.
[0036] This description includes part or all of the content as
disclosed in the description and/or drawings of Japanese Patent
Application No. 2010-042669, which is a priority document of the
present application.
BRIEF DESCRIPTION OF THE DRAWINGS
[0037] FIGS. 1A and 1B show a distal end of a
coaxial-light-emission catheter. FIG. 1A shows a front view and
FIG. 1B shows a side view.
[0038] FIG. 2 is a cross-sectional view of a distal end of a
coaxial-light-emission catheter.
[0039] FIG. 3 is a side view of a distal end of a
lateral-light-emission catheter.
[0040] FIG. 4 is a cross-sectional view of a distal end of a
lateral-light-emission catheter comprising a mirror. An electrode
may serve as a mirror.
[0041] FIG. 5 is a cross-sectional view of a distal end of a
lateral-light-emission catheter comprising a prism. In FIG. 5,
there is an air-containing space surrounded by a light-emitting
window 2, an electrode 3, and a prism 6a.
[0042] FIG. 6 is a cross-sectional view of a distal end of a
lateral-light-emission catheter comprising a GRIN lens.
[0043] FIGS. 7A-7E show configurations of markers for monitoring
the direction of laser beam emission. FIG. 7A to FIG. 7C each show
a catheter comprising two markers 7 mounted thereon in a diagonal
manner relative to the axial direction of the catheter, FIG. 7D
shows a catheter comprising two markers 7 mounted thereon in an
approximately vertical manner relative to the axial direction of
the catheter, and FIG. 7E shows a catheter comprising two markers 7
mounted thereon in an asymmetric manner when observed from the
side.
[0044] FIGS. 8A and 8B show the whole catheter according to the
present invention.
[0045] FIG. 8A shows an extended catheter end and FIG. 8B shows a
bent catheter end. In FIG. 8A, A-A represents a cross-sectional
view.
[0046] FIG. 9 schematically shows a photodynamic ablation apparatus
used for cardiac muscle tissue comprising the catheter of the
present invention.
[0047] FIG. 10 shows an experimental system for blocking electric
conduction in the cardiac muscle by photodynamic therapy using
cardiac muscle tissue excised from a rat.
[0048] FIG. 11 shows a positional relationship among the
electrically-stimulated site, the measuring electrode, and the
laser beam irradiated site in an experiment for blocking electric
conduction in the cardiac muscle by photodynamic therapy using
cardiac muscle tissue excised from a rat.
[0049] FIGS. 12A and 12B show waveforms of transmitted stimulus at
the measuring electrodes A and B measured in the experiment for
blocking electric conduction in the cardiac muscle by photodynamic
therapy using cardiac muscle tissue excised from a rat. FIG. 12(a)
shows a waveform observed before photodynamic therapy and FIG.
12(b) show a waveform observed 5 minutes after photodynamic
therapy.
[0050] FIG. 13 shows an experimental system for verification of
immediate conduction blocking using swine.
[0051] FIG. 14 shows the positions of a laser beam irradiated site
and an electrode in cardiac muscle tissue in an experiment for
verification of immediate conduction blocking using swine.
[0052] FIG. 15 shows an electric potential waveform outside the
cells at the electrode B before and after laser beam irradiation in
an experiment for verification of immediate conduction blocking
using swine.
[0053] FIG. 16 shows therapeutic effects deduced based on the
electric potential waveform at an electrode when it is included in
the laser beam emission site.
[0054] FIG. 17 shows therapeutic effects deduced based on the
electric potential waveform at an electrode when it is not included
in the laser beam emission site.
EMBODIMENTS FOR CARRYING OUT THE INVENTION
[0055] Hereafter, the present invention is described in detail.
[0056] The catheter that performs photodynamic ablation of cardiac
muscle tissue using photodynamic therapy according to the present
invention is capable of permanently blocking abnormal electrical
conduction in cardiac muscle tissue. For example, tachyarrhythmia
and atrial fibrillation are treated by permanently blocking
abnormal electrical conduction (electrical entrance) in the
tissue.
[0057] The term "PDT," which can be used interchangeably with
photodynamic therapy or photochemical therapy, used herein refers
to a therapeutic method utilizing photochemical reactions that
damage and destroy lesions through the presence of a
photosensitizer (a PDT agent; an agent for photodynamic therapy)
and a light beam capable of exciting an agent for photodynamic
therapy.
[0058] The catheter of the present invention comprises a
light-emission site, and it is capable of emitting a light beam
from the light-emission site. The catheter is inserted into the
heart through a major vein or artery, an agent for photodynamic
therapy is administered to a target site of cardiac muscle tissue,
and the target site is irradiated with a laser beam so as to
destroy the target tissue. The catheter of the present invention
can be used and operated in the blood vessel or cardiac lumen. The
blood vessel is preferably of the heart.
[0059] The term "catheter" refers to a tubule that can be inserted
into a blood vessel. The catheter of the present invention
comprises a light transmission means inserted into the tubule or
provided in the tubule.
[0060] In the present invention, the term "abnormal electrical
conduction" in cardiac muscle tissue can be used interchangeably
with "reentry," whereby electrical excitation occurring in cardiac
muscle is not transmitted unidirectionally but rather turns in the
vicinity of (excitation reentry). Reentry is classified as
anatomical reentry, which is caused by a specific heart tissue
structure, and functional reentry, which can occur at any cardiac
muscle tissue site in the heart due to decreased cardiac muscle
conduction at a local region and increased nonuniformity of
refractory period (time during which, after electrical excitation
of cardiac muscle cells occurs once, no response occurs even with
an inflow of an electrical stimulus).
[0061] An example of the former is atrioventricular nodal reentrant
tachycardia (AVNRT) in which reentry occurs when the
atrioventricular node has a fast conduction pathway and a slow
conduction pathway. Further, reentry caused by occurrence of an
accessory conduction pathway between the atrium and the ventricle
that is different from the original conduction pathway and passes
through the Kent bundle is also a representative form of anatomical
reentry, and it causes Wolff-Parkinson-White syndrome (WPW
syndrome).
[0062] An example of the latter is reentry that causes persistent
atrial fibrillation and occurs at any position on the atrium.
Furthermore, examples of abnormal electrical excitation include
abnormal automaticity and triggered activity. Cardiac muscle cells
in atriums and ventricles (working myocardium) naturally have an
autonomous excitation function (automaticity), and electrical
excitation is usually controlled by the sinoatrial node and the
atrioventricular node at superior positions (referred to as
"special cardiac muscles"). When resting potential becomes shallow
for some reason, automaticity may occur in the working myocardium.
This phenomenon is referred to as "abnormal automaticity." The
phenomenon of electrical excitation occurring at abnormal timings
due to a membrane potential change that occurs during the course of
repolarization (after action potential is exhibited, potential
settles at original resting potential) of an action potential
(potential when the membrane potential of a cardiac muscle cell
becomes higher than resting potential due to depolarization) (early
after depolarization: EAD) and a membrane potential change that
occurs after completion of repolarization (delayed after
depolarization: DAD) is referred to as "triggered activity." Such
abnormal electrical excitations can cause various arrhythmic
conditions. Hyperexcitability from the left atrium to the entrance
of the pulmonary vein, which is said to be a major cause of atrial
fibrillation, is considered to be either abnormal automaticity or
triggered activity, and such excitations are collectively referred
to as "focal activity" (local focal excitation).
[0063] An abnormal electrical conduction site in the cardiac muscle
can be treated by photodynamic ablation using the catheter of the
present invention. Treatment of an abnormal electrical conduction
site in the cardiac muscle via photodynamic ablation may be
occasionally referred to as blocking of abnormal electrical
conduction, blocking of an abnormal electrical conduction pathway,
blocking of reentry (accessory conduction pathway), or formation of
an abnormal electrical conduction block. When the above-mentioned
automaticity is formed at a site other than the sinoatrial node and
the atrioventricular node, further, the site may be referred to as
a site at which hyperexcitability occurs or a site having abnormal
automaticity. The site at which hyperexcitability occurs is also a
site that generates excess electrical signals in the stimulus
transmission system. A site having such a site at which
hyperexcitability occurs can be necrotized by photodynamic ablation
using the catheter of the present invention. In such a case,
abnormal electrical conduction in the cardiac muscle is blocked by
necrotizing the site at which hyperexcitability occurs.
Accordingly, such a case may also be referred to as blocking of
abnormal electrical conduction.
[0064] Diseases that can be treated using the catheter of the
present invention include arrhythmia caused by the presence of the
above-mentioned abnormal electrical conduction site or site at
which hyperexcitability occurs, and in particular, tachyarrhythmia.
Examples of such tachyarrhythmia include paroxysmal
supraventricular tachycardia (PSVT), such as atrioventricular
reentrant tachycardia (AVRT; WPW syndrome) and atrioventricular
nodal reentrant tachycardia (AVNRT), and atrial flutter, atrial
tachycardia, atrial fibrillation (AF) (which are examples of
supraventricular tachyarrhythmia), and ventricular tachyarrhythmia,
such as ventricular tachycardia.
[0065] In the case of atrioventricular reentrant tachycardia, an
accessory conduction pathway connecting the ventricle and the
atrium exists in addition to the atrioventricular node and the His
bundle. Thus, an electrical signal that has been transmitted to the
ventricle returns to the atrium. In the case of atrioventricular
nodal reentrant tachycardia, no accessory conduction pathway
exists. However, a conduction pathway of loop electrical signals is
formed with a fast route and a slow route because of differences in
the speed of transmission of the electrical signal inside one
atrioventricular node. Since the electrical signal continues to
circulate in the atrioventricular node and alternately stimulates
the atrium and ventricle, tachyarrhythmia develops. Atrial flutter
is caused by abnormal electrical activity in which an electrical
signal continues to circulate in the right atrium in circle. In the
case of atrial tachycardia, a site at which hyperexcitability
occurs exists in the atrium. Atrial fibrillation is caused by
hyperexcitable conduction in the left atrium-pulmonary vein
junction. Ventricular tachycardia is caused by looped abnormal
electrical signal transmission that occurs in the vicinity of the
cardiac muscle damaged by myocardial infarction or the like.
[0066] The application range of ablation is specified by the
Japanese Circulation Society (Guidelines for Diagnosis and
Treatment of Cardiovascular Diseases, Guidelines for
Non-Pharmacotherapy of Cardiac Arrhythmias, Jpn. Circulation J 65
(Suppl. V): 1127, 2001), and a target of the therapy can be
selected based on such guidelines.
[0067] Accordingly, the site subjected to photodynamic ablation
using the catheter of the present invention is the above-mentioned
abnormal electrical conduction site or site at which
hyperexcitability occurs in the cardiac muscle, which causes
arrhythmia. Examples thereof include portions of the cardiac muscle
including the atrium such as the atrial septum, the ventricle, the
atrial wall, a portion of the ventricular wall and the coronary
sinus, a portion of the superior and inferior vena cava, and a
portion in the vicinity of the junction of the vein and the cardiac
muscle. The site subjected to photodynamic ablation can be suitably
determined based on the type of arrhythmia, and an abnormal
electrical conduction site or site at which hyperexcitability
occurs that causes arrhythmia can be determined by mapping. Thus,
the site can be subjected to photodynamic ablation. Photodynamic
ablation can be performed in a linear or dotted manner, which can
be suitably determined based on the target photodynamic ablation
site.
[0068] For example, some tissues of the target abnormal left atrium
exist in a region in which electrical excitation that causes an
attack of atrial fibrillation is conducted to the left atrium.
Examples of such region include a portion of the cardiac muscle in
the vicinity of the junction between the pulmonary vein (PV) and
the left atrium in the heart. The cardiac muscle portion at the
junction of the pulmonary vein and the left atrium corresponds to a
portion in the vicinity of the entrance of the pulmonary vein. The
portion in the vicinity of the junction between the pulmonary vein
and the left atrium in the heart is preferable. When tissue in the
vicinity of the junction between the pulmonary vein and the cardiac
left atrium is destroyed, for example, electrical connection
between the left atrium and the pulmonary vein is eliminated (i.e.,
a conduction block is formed), the pulmonary vein is electrically
isolated, excitation is not conducted, and atrial extrasystoles
originating in the pulmonary vein, which causes atrial
fibrillation, disappear. In such a case, a portion of the junction
between the pulmonary vein and the cardiac left atrium may be
destroyed, but the entire circumference is preferably treated using
the apparatus of the present invention to destroy significant
portions of the region in the circumferential direction of the
tissue. Alternatively, tissues at the junction of two pulmonary
veins (i.e., the superior and inferior pulmonary veins) and the
left atrium may be individually destroyed, or two veins may be
enclosed and destroyed collectively. Further, tissue at the
junction of four pulmonary veins and the left atrium may be
enclosed and destroyed collectively. When the pulmonary vein is
isolated, tissue is preferably destroyed continuously in a linear
manner. The catheter used for photodynamic ablation in photodynamic
therapy of the present invention is suitable for continuous
photodynamic ablation in a linear manner.
[0069] In addition to the isolation of the pulmonary vein, the
canopy of the left atrium and the isthmus between mitral annular
rings may be destroyed in a linear manner for the treatment of
atrial fibrillation.
[0070] In the present invention, blocking of electrical conduction
from the above-mentioned pulmonary vein to the left atrium may be
expressed as "formation of a conduction block between the left
atrium and the pulmonary vein" or "performance of photodynamic
ablation for electrical pulmonary vein (PV) isolation." The
procedure for enclosing and destroying tissue at the junction of
four pulmonary veins and the left atrium collectively may be
referred to as the Box Isolation technique.
[0071] The catheter of the present invention comprises a light beam
transmission pathway as a light beam transmission means for
transmitting a light beam to a distal end of the catheter. The
distal end of the catheter is equipped with a light-transmissive
light-emitting window for emitting the light beam transmitted by
the light beam transmission means toward the target site. In the
present invention, the "light-emitting window" may be occasionally
referred to as a "light-emitting site." The catheter of the present
invention further comprises at least two electrodes at the distal
end.
[0072] The thickness of the catheter of the present invention is 5
to 9 Fr and it is preferably 6 to 8 Fr. The light transmission
pathway is positioned inside the catheter so as to avoid direct
contact with tissue. The light beam that has passed through the
light transmission pathway is emitted from the light-emitting
window and then the target site is irradiated with the light beam
(i.e., cardiac muscle tissue). The end of the catheter of the
present invention may have a structure that freely bends. To this
end, for example, a tension wire can be provided in the catheter,
and the end can be bent by pulling of the tension wire.
Furthermore, the end may have been bent beforehand so as to match
the shape of a treatment site. A catheter that is generally used as
a heart catheter can be used. The catheter of the present invention
may comprise a guide sheath or a guide wire for achieving the
insertion of a catheter into the target site.
[0073] The light beam emitted from the end of the light beam
transmission pathway is emitted to the outside of the catheter
through the light-emitting window and the target site is
irradiated. The light-emitting window is provided in the vicinity
of the distal end of the catheter. A region "in the vicinity of the
distal end" is a region near the end located on the opposite side
of the end connected to the light beam generator (the proximal
end), and such expression refers to the distal end and the region
within about several tens centimeters from the distal end. For
example, the light-emitting window is provided at the end of the
catheter or a side in the vicinity of a distal end of the catheter.
When the light-emitting window is provided at an end of the
catheter, for example, light is emitted coaxially with the
catheter. When the light-emitting window is provided on a side in
the vicinity of a distal end of the catheter, light is emitted
laterally relative to the axial direction of the catheter. When
light is emitted laterally, the direction (angle) of emission is
not limited. Light may be emitted in a vertical direction or in a
diagonally forward direction relative to the long axial direction
of the catheter. When light is emitted at an angle of 0.degree. to
90.degree. relative to the long axial direction of the catheter
designated as the standard (0), in general, such emission is
referred to as "lateral light emission." The direction of light
emission refers to the direction of the central axis of a laser
beam (i.e., the direction of the luminous flux). The former type is
referred to as a coaxial-light-emission catheter and the latter
type is referred to as a lateral-light-emission catheter. The
catheter of the present invention may be capable of coaxial and
lateral light emission. Light-emitting windows may be provided both
at the end of the catheter and a region in the vicinity of the
distal end. The light-emitting window is composed of a
light-transmissive material. Examples of such materials include
glass, such as quartz glass, sapphire glass, and BK7 (borosilicate
crown optical glass), and transparent resins. Such light-emitting
window may be occasionally referred to as an "optical window" in
the present invention. The light-emitting window may have functions
of condensing light emitted from the end of a laser transmission
pathway, scattering the light, or changing the direction of
emission. The configuration of the light-emitting window is not
limited, provided that the light beam emitted through the light
beam transmission pathway inside the catheter is transmitted
therethrough and emitted to the outside of the catheter. For
example, the light-emitting window can be in the form of a plate,
lens, cube, or cylinder (column). Specifically, the light-emitting
window is made of an optical lens such as a concave or convex lens,
a gradient index lens such as a GRIN lens, an optical element such
as a prism or mirror, or a liquid material, for example. The
surface of the light-emitting window is made from a material or has
a structure that suppresses interfacial reflection of substances
having different refractive indexes. An example of a substance that
suppresses interfacial reflection is an index-matching material.
Specific examples include antireflection coatings, such as matching
oil and AR coating. An example of a structure that suppresses
reflection is a nanostructure that is smaller than an optical
wavelength. Specific examples of light-emitting windows include the
light-emitting windows of the catheters exemplified in FIG. 1 and
FIG. 3. The light-emitting window of the catheter shown in FIG. 1
is in a cylindrical form with a spherical end. The catheter shown
in FIG. 1 is a coaxial-light-emission catheter. FIG. 1B shows a
side view when the catheter end is designated as the front, and
Fig. 1A shows a front view. FIG. 2 is a cross-sectional view. The
catheter shown in FIG. 3 is a lateral-light-emission catheter,
which has a ring-shaped light-emitting window. FIG. 4 shows a
cross-sectional view of a distal end of the catheter having a
ring-shaped light-emitting window. A plate-like light-emitting
window can also be used. Such plate-like light-emitting window may
have a certain degree of curvature relative to a curve of the
catheter. When a plate-like light-emitting window with a certain
degree of curvature surrounds the entire catheter, the
light-emitting window has a ring shape.
[0074] The catheter of the present invention comprises at least two
electrodes. Such electrodes function at least as electrodes for
potential measurement. The catheter of the present invention may
comprise a conducting electrode. The electrode for potential
measurement may also serve as a conducting electrode.
Alternatively, a conducting electrode used only for conduction may
be provided separately from an electrode for potential measurement
used only for potential measurement. The catheter of the present
invention is required to comprise at least two electrodes for
potential measurement.
[0075] The conducting electrode is capable of passing an electric
current to a site with which the electrode is in contact. Such
conducting electrode is connected to a lead wire provided inside
the catheter, and it is then connected to a power unit through the
lead wire. The conducting electrode can be used for conducting
electricity to the target site to heat and necrotize such site. The
catheter of the present invention performs photodynamic ablation of
cardiac muscle tissue via photochemical reactions, and ablation can
also be carried out with heating with the supplemental use of a
conducting electrode.
[0076] An electrode for potential measurement can be used for
measuring potential at a target site with which the electrode is in
contact. There are at least two electrodes for potential
measurement, and these electrodes are located in such a manner that
they are capable of measuring potential at sites on both sides of
cardiac muscle tissue that has been subjected to ablation with the
light beam emitted from the light-emitting window, and potential
differences between such sites. Specifically, at least two
electrodes for potential measurement are provided in the periphery
of the light-emitting window so as to sandwich the same. The
electrodes may be provided in the periphery of the light-emitting
window while they are in contact with the light-emitting window.
Alternatively, the electrodes may be located within a short
distance from the light-emitting window without being in direct
contact therewith. For example, the electrodes may be provided
within 5 mm and preferably within 1 mm from the light-emitting
window. Also, the electrodes sandwich the light-emitting window in
such a manner that the light-emitting window is located on a line
connecting an electrode to another electrode among a plurality of
electrodes for potential measurement. The light-emitting window may
be provided with a window frame used for mounting the
light-emitting window on the catheter. When a window frame is
provided, electrodes for potential measurement may be provided on
the window frame. Also, an electrode for potential measurement may
serve as a window frame. The term "at least two electrodes"
mentioned above refers to, for example, 2, 3, 4, 5, or more
electrodes, and 2 electrodes are preferable. Alternatively,
electrodes for potential measurement may be provided in regions
other than the periphery of the light-emitting window. For example,
a plurality of electrodes may be provided outside the distal end of
the catheter. In such a case, for example, ring-shaped electrodes
surrounding the periphery of the catheter can be used. When a
plurality of such ring-shaped electrodes are provided, the
distances between ring-shaped electrodes are approximately within
10 mm, and preferably within 5 mm. Also, the electrode
configurations are not limited to those mentioned above, and an
electrode may be in the form of a line, plane, ribbon, cylinder,
dome, or the like. A plane form may be a flat or curved plane. For
example, a coaxial-light-emission catheter shown in FIG. 1 has two
planar electrodes on the outer circumference of the catheter end.
In this case, such two electrodes are referred to as the first
electrode and the second electrode. A lateral-light-emission
catheter shown in FIG. 3 has a round-nose cylinder-shaped
(dome-shaped) electrode located preferably in the vicinity of a
distal end, and more preferably at a site closer to the distal end
than the light-emitting window, and a ring-shaped electrode at a
site closer to the proximal end than the light-emitting window. In
such a case, an electrode provided preferably in the vicinity of
the distal end, and more preferably at the distal end, is referred
to as the first electrode, and a ring-shaped electrode provided at
a proximal site is referred to as the second electrode. The
electrode material may be an SUS material. Use of materials that
would not adversely affect organisms is preferable. Examples
thereof include gold, silver, platinum, tungsten, and palladium,
alloy of any thereof, and Ni--Ti alloys, and titanium platinum.
[0077] The electrodes for potential measurement can be connected to
a potential measuring instrument through a lead wire and used to
measure potential. In such a case, two counter electrodes may be
used and potential differences between two electrodes may be
measured. Alternatively, a reference electrode is separately
provided in another site, such as the surface of the outer skin of
a subject, and potential relative to the reference electrode may be
measured. With the use of at least two electrodes for potential
measurement, potential differences between two points of cardiac
muscle tissue that sandwich the site subjected to photodynamic
ablation via photochemical reactions can be measured.
[0078] When cardiac muscle tissue is necrotized by photodynamic
ablation, electrical conduction becomes difficult or impossible at
the necrotized site. With reference to FIG. 16 and FIG. 17, changes
in the electric conductivity of cardiac muscle tissue deduced based
on electric potential waveforms at the electrodes are described in
two ways; that is, a case in which the potential measuring site
includes the photodynamic ablation site and a case in which it does
not include the photodynamic ablation site. A case in which two
electrodes are used is considered herein.
[0079] A case in which an electrode is included in a light emission
site is first described. When there are two electrodes A and B,
electrical signals transmitted at given speeds are first measured
at electrode A and then at electrode B. Electrical signals are
transmitted in cardiac muscle tissue in the manner as shown in FIG.
16(a) prior to photodynamic ablation. When electric conductivity
begins to disappear because of photodynamic ablation in the
vicinity of the electrodes, amplitudes in the electric potential
waveforms observed at electrode A and electrode B decrease, as
shown in FIG. 16(b). Since electrical signals are not transmitted
if electric conductivity is completely lost in cardiac muscle
tissue as shown in FIG. 16(c), amplitudes in electric potential
waveforms also disappear. A case in which an electrode is not
included in a light emission site is described next. Electrical
signals are transmitted in cardiac muscle tissue in the manner as
shown in FIG. 17(a) prior to photodynamic ablation. When electric
conductivity begins to disappear because of photodynamic ablation
in a region between two electrodes, electrical signals are
transmitted while bypassing the site at which electric conductivity
has disappeared as shown in FIG. 17(b). This generates a temporal
difference (delay) in the electric potential waveform at electrode
B, compared with that prior to photodynamic ablation. Since
electrical signals are not transmitted if electric conductivity is
lost across all the cardiac muscle tissue wall layers as shown in
FIG. 17(c), electrical signals are not detected at electrode B.
[0080] Thus, potential may be measured using at least two
electrodes for potential measurement, so that photodynamic ablation
effects at a site subjected to photodynamic ablation via
photochemical reactions can be evaluated. When three or more
electrodes for potential measurement are provided, amplitudes in
the electric potential waveforms or delays in electric transmission
among any of three or more points can be measured, and photodynamic
ablation effects can be more precisely evaluated.
[0081] When photodynamic ablation is performed via photochemical
reactions, it is preferable that the catheter end be bent at the
time of light beam emission, so that the target site is irradiated
with the light beam. When the catheter end is brought into contact
with cardiac muscle tissue upon bending, changes occur in the
potential measured with electrodes for potential measurement. This
enables the judgment regarding the occurrence of contact. Judgment
regarding the occurrence of contact also enables judgment regarding
whether or not the catheter end is positioned in the correct
direction relative to the target site.
[0082] It is preferable that a light transmission means provided
inside the catheter be an optical fiber with light conductivity of
90% or higher. A quartz optical fiber or plastic fiber is
preferably used. An optical fiber is provided inside the catheter,
and at least one optical fiber is used. When a plurality of optical
fibers are used, a plurality of optical fibers exerting the same
functions, optical fibers used for excitation light of
photosensitive pigments and optical fibers for receiving the light
returned therefrom or fluorescence, optical fibers for coaxially
emitting light beam, optical fibers for laterally emitting light
beam, and optical fibers for diagonally emitting light beam, or
optical fibers for transmitting light beams with different
wavelengths, are used. The outer diameter of an optical fiber used
is 100 .mu.m to 400 .mu.m, and preferably 200 .mu.m to 300 .mu.m.
The core diameter of an optical fiber used is 50 .mu.m to 300
.mu.m, and preferably 100 .mu.m to 200 .mu.m. The numerical
aperture (NA) of an optical fiber is 0.1 to 1, and preferably 0.2
to 0.5. The diameter of laser beam emission on the window surface
at the catheter end is 0.2 mm to 3 mm, and preferably 1 mm to 2.5
mm. When cardiac muscle tissue, blood, physiological saline,
high-molecular-weight dextran, or contrast medium is used as a
medium through which the light emitted from the light-emitting
window passes toward the target site, the laser beam emission solid
angle is 3.degree. to 60.degree., and preferably 5.degree. to
45.degree. at the catheter end. An end of an optical fiber is
connected with a light beam generator, and an optical fiber is
capable of transmitting the light beam generated by the light beam
generator to the target site.
[0083] An optical fiber may or may not be in contact with the
light-emitting window. When the light-emitting window is provided
at the catheter end and the light beam transmitted through an
optical fiber is emitted through the light-emitting window composed
of a lens along the axial direction of the catheter or the
transmitted light beam is emitted through the light-emitting window
composed of a prism in a lateral direction instead of a long axial
direction of the catheter, for example, an optical fiber may be
brought into contact with the light-emitting window to reduce light
loss resulting from diffusion or reflection. When an optical fiber
is in contact with the light-emitting window, the contact surfaces
are a plane surface and a plane surface, a curved surface and a
curved surface, a plane surface and a curved surface, or a convex
surface and a concave surface. The contact surfaces of the optical
fiber and the light-emitting window are made of substances or have
structures that suppress the interface reflection of substances
having different refractive indexes. A specific example of a
substance that suppresses reflection is an index-matching material.
More specifically, such substance can be an antireflection coating,
such as matching oil or AR coating. An example of a structure that
suppresses reflection is a nanostructure that is smaller than an
optical wavelength. When the light beam transmitted through an
optical fiber provided inside the catheter is emitted laterally
instead of along the long axial direction of the catheter using a
mirror, the light beam emitted from the optical fiber reflects off
the mirror, and the target site is then irradiated through the
light-emitting window. Accordingly, the optical fiber is not
necessarily in contact with the light-emitting window. When the
light is emitted laterally, as shown in FIG. 4, a mirror may be
fixed at a given angle inside the catheter at its distal end, so
that the light beam emitted from the end of the optical fiber
reflects off the mirror and is then emitted to the outside through
the light-emitting window. In such a case, an electrode may be
integrated with a mirror; that is, an electrode may serve as a
mirror. The angle for mounting a mirror may be adjusted, so that a
light beam can be laterally emitted at an arbitrary angle. While
the catheter shown in FIG. 4 uses a mirror, it is sufficient for
the catheter to contain inside itself a construct such as an
optical component or element capable of reflecting a light in an
arbitrary direction. For example, a prism may be used instead of a
mirror (FIG. 5), or a mirror may be provided on a light-reflecting
surface of a prism. Also, a gradient index lens such as a GRIN lens
may be used (FIG. 6) to emit a light beam in a lateral direction.
Further, a mirror, a prism, and a lens may be used in combination.
Use of such components in combination enables the light beam
emission direction to be changed in two steps, for example. In such
a case, the same components may be used in combination, or
different components, such as a mirror and a prism, a mirror and a
lens, a lens and a prism, or a mirror, a prism, and a lens, may be
used in combination. In order to reduce the influence at the
interface on the optical pathway along which the light beam emitted
from the end of an optical fiber reflects and reaches the
light-emitting window located on the side, the light-emitting
window may be in the form of a container, a mirror may be provided
in such container, and a liquid material, such as a solution, may
be introduced thereinto. Further, the light-emitting window may be
a transparent solid comprising a mirror embedded therein. In such a
case, a window may be prepared from transparent resin, and a mirror
for reflecting a light beam may be embedded therein at the time of
preparation. Furthermore, the internal structure of the catheter
may be designed so as to reflect light, and an optical fiber may be
processed (e.g., diagonal sanding) to form a refractive surface
from which a light beam reflects.
[0084] Hereafter, the catheter of the present invention is
described with reference to FIGS. 1 to 6. It should be noted that
the catheter described herein is merely an example and the catheter
of the present invention is not limited to the catheters shown in
FIGS. 1 to 6.
[0085] The catheter 1 shown in FIGS. 1 and 2 comprises an optical
fiber 4 inside itself and a light-emitting window 2 made of a
cylindrical optical element at the end thereof. The catheter 1
shown in FIGS. 1 and 2 emits a light beam along the long axis
thereof. The optical fiber 4 is in contact with the light-emitting
window 2, a light beam transmitted through the optical fiber 4
passes through the light-emitting window 2 while suppressing loss
caused by reflection or scattering, and the light beam is then
emitted to the outside. The periphery of the light-emitting window
2 is covered with a window frame. The window frame is connected to
the catheter, and the light-emitting window 2 is fixed to the
catheter 1 with the aid of the frame. When the light beam emitted
through the optical fiber 4 passes through the inside of the
optical window 2, the light beam is partially applied to the window
frame that covers the side of the light-emitting window 2. If the
light beam is absorbed by the window frame, the efficiency of light
beam irradiation of the target site becomes lowered. Accordingly,
it is preferable that the window frame covering the light-emitting
window 2 be made of a material that reflects light beams or the
inner surface thereof be coated with a material that reflects light
beams. Use of a material having 90% or higher optical reflectivity
of light at a wavelength of 600 nm to 700 nm is preferable.
Examples of such materials include gold, silver, aluminum, copper,
and dielectric substances. The optical reflectivity of gold,
silver, aluminum, and copper of light having a wavelength of 700 nm
is 95.5%, 98.3%, 90.3%, and 96.6%, respectively. Coating may be
provided by forming a thin film of such metal on a surface by means
of plating, sputtering, vapor deposition, or other means. The inner
surface of the window frame may be treated to be glossy, so that
the light undergoes specular reflection. Alternatively, surface
roughness may be retained, so that the light undergoes diffuse
reflection. It is preferable that the inner surface of the window
frame have a specular finish. When a lateral-light-emission
catheter allows a light beam to reflect off a mirror, it is
preferable that a mirror surface be coated with any of the
materials having high reflectivity mentioned above.
[0086] Further, the window frame is provided with at least two
electrodes 3 for potential measurement. As shown in FIG. 1A, for
example, the electrodes for potential measurement 3 may be provided
at both sides of the light-emitting window 2 opposite to each other
in such a manner that the two electrodes 3 partially cover the
exterior of the window frame. Since the electrodes 3 for potential
measurement are used for measuring the potential in the vicinity of
the target site of cardiac muscle tissue, it is necessary to bring
the electrodes into contact with an area in the vicinity of the
target site of cardiac muscle tissue. To this end, the electrodes
are provided at the end of the catheter. The electrode 3 is
connected to a lead wire, the electrode 3 is then connected to a
potential measuring instrument through the lead wire, and potential
at the target site into contact with which the electrodes 3 for
potential measurement had been brought can then be measured.
[0087] The catheter shown in FIGS. 3 to 6 is a
lateral-light-emission catheter comprising an optical fiber 4
inside itself and a light-emitting window 2 made of an optical
element on the lateral side of the catheter distal end. In the case
of the catheter shown in FIG. 4, the light beam emitted through an
optical fiber reflects off the mirror 5 and is emitted to the
outside through the light-emitting window 2. In the case of the
catheter shown in FIG. 5, the light beam emitted through an optical
fiber is deflected by a prism 6a, and it is emitted to the outside
through the light-emitting window. In the case of the catheter
shown in FIG. 6, the light beam emitted through an optical fiber is
deflected by a GRIN lens 6b, and it is emitted to the outside
through the light-emitting window 2. At least two electrodes 3 for
potential measurement can be provided in the periphery of the
light-emitting window 2 so as to sandwich the window in the case of
such lateral-light-emission catheter, and potentials at two points
of cardiac muscle tissue can then be measured. The
lateral-light-emission catheter shown in FIG. 3 comprises a
dome-shaped electrode 3 at its end and a ring-shaped electrode 3 on
the opposite side of the light-emitting window.
[0088] The catheter of the present invention may further comprise a
means for monitoring the direction of light beam emission from
outside of a body. Such means is capable of external detection when
a catheter is inserted into the body. An example of such means is a
radiopaque marker mounted at a site in the vicinity of the distal
end of the catheter, so that the direction of a light beam being
emitted; i.e., the position of the light-emitting window, can be
detected. Preferably, the marker is in the form of a line, plane,
ribbon, or ring, and it is mounted along the outer circumference of
the distal end of the catheter. In such a case, the marker may be
provided to intersect the long axis of the catheter. The marker may
be preferably mounted on the catheter in a diagonal manner at a
given angle relative to the long axial direction of the catheter.
Alternatively, a marker may be mounted in an asymmetric manner when
a marker mounted in an area in the vicinity of the distal end of
the catheter is observed from the lateral direction. FIG. 7 shows
an example of a marker mounted on the catheter at its distal end.
FIG. 7A to FIG. 7C each show a catheter comprising two markers 7
mounted thereon in a diagonal manner relative to the axial
direction of the catheter, FIG. 7D shows a catheter comprising two
markers 7 mounted thereon in an approximately vertical manner
relative to the axial direction of the catheter, and FIG. 7E shows
a catheter comprising two markers 7 mounted thereon in an
asymmetric manner when observed along the lateral direction. The
configuration of the marker 7 is associated with the position of
the window through which the light is emitted from the catheter,
and the direction of light beam emission can be detected by
observing the marker. For example, the catheter shown in FIG. 7A to
FIG. 7C is a lateral-light-emission catheter comprising two markers
7 mounted thereon in a diagonal manner relative to the long axial
direction of the catheter. Such catheter emits the light beam 8 in
a diagonally forward direction, and the light beam 8 is emitted in
a linear direction of the marker 7 mounted in a diagonal manner on
the catheter. The catheter shown in FIG. 7D is a
lateral-light-emission catheter, which comprises two markers 7 in
an approximately vertical manner relative to a long axial direction
of the catheter. Such catheter emits the light beam 8 in a long
axial direction of the marker 7. In FIG. 7E, two markers 7 are
asymmetric when observed from the lateral side, and the thickness
of a marker 7 differs from that of the other marker 7 along the
long axis of the catheter. The light beam 8 is emitted laterally in
the direction in which the marker 7 becomes thickened. When a
marker that monitors the direction of light beam emission is
mounted, the direction of emission can be targeted to the site of
treatment. An X-ray impermeable metal can be used as a radiopaque
marker, and platinum, gold, iridium, and an alloy of such metals
used in combination are preferable from the viewpoint of
biocompatibility. When the apparatus of the present invention
comprises a catheter, for example, at least one radiopaque marker
(e.g., 2, 3, or more) may be provided at a distal end of the
catheter. Also, a marker may serve as an electrode for potential
measurement. When a plurality of markers are provided, at least one
marker functions as an electrode for potential measurement.
[0089] FIG. 8 shows an overall view of the catheter of the present
invention.
[0090] The catheter of the present invention is inserted into the
heart through blood vessels, and it can be used in the cardiac
lumen in the presence of blood. In such a case, the light beam
emitted from the catheter passes through the inside of the blood
for a short distance and reaches the target site. In such a case,
physiological saline, polymeric dextran, a contrast medium, a
liquid containing artificial erythrocytes, or the like is injected
into the cardiac blood vessels through the catheter end, and the
light beam may be emitted using such liquid as a medium.
[0091] When photodynamic therapy is performed, administration of a
sensitizer (e.g., an agent for photodynamic therapy or
photosensitive pigment) is necessary. Agents for photodynamic
therapy that are to be used in combination with the apparatus of
the present invention are not limited, and a known agent for
photodynamic therapy can be used in combination with a light beam
at an absorption wavelength thereof. Adequate agents for
photodynamic therapy and light beam types may be selected. Any
agent for photodynamic therapy can be selected from agents for
photodynamic therapy having an absorption wavelength at about 630
nm to those having longer absorption wavelengths. For the treatment
of arrhythmia, use of an agent for photodynamic therapy that can be
easily eliminated from cardiac muscle cells is preferable. Since it
is desirable to perform light beam irradiation before an agent for
photodynamic therapy is taken up into cells, use of an agent for
photodynamic therapy that can remain in the extracellular matrix
for a long period of time is preferable. Thus, water-soluble agents
for photodynamic therapy are suitable for the treatment of
arrhythmia. Examples of such agents for photodynamic therapy
include chlorine-based agents for photodynamic therapy having
chlorine skeletons, such as ATX-S10 (670 nm) (iminochlorin aspartic
acid derivative, Oriental Menthol Industry Ltd., rights were
transferred to Photochemical Co., Ltd. in 2000, JP Patent
Publication (Kokai) No. 6-80671 A (1996)), NPe6 (664 nm)
(talaporfin sodium, Laserphyrin.RTM., mono-L-aspartyl chlorine 6,
JP Patent No. 2961074), mTHPC (652 nm), SnET2 (660 nm) (tin
etiopurpurin, Miravant Medical Technologies), A1PcS (675 nm)
(chloroaluminium sulphonated phthalocyanine), BPD-MA (690 nm)
(benzoporphyrin derivative monoacid ring A, QLT Inc.), and Lu-tex
(732 nm) (Lutetium Texaphyrin), with talaporfin sodium being
particularly preferable. The agent for photodynamic therapy is
dissolved in an appropriate buffer such as a phosphate-buffered
saline solution, pharmaceutically acceptable additives are added
thereto according to need, and the resulting mixture is
administered. Examples of additives include solubilizers, such as
organic solvents, pH modifiers, such as acids and nucleotides,
stabilizers, such as ascorbic acids, excipients, such as glucose,
and isotonizing agents for photodynamic therapy, such as sodium
chloride.
[0092] An agent for photodynamic therapy for performing
photodynamic therapy is preferably administered by intravenous
injection to a subject to be treated in advance. The agent for
photodynamic therapy may be administered by supplying a
highly-concentrated agent for photodynamic therapy through a
catheter placed in a specific blood vessel, such as the coronary
artery to the cardiac muscle. In this case, the apparatus of the
present invention comprises a means for supplying an agent for
photodynamic therapy (i.e., an apparatus for supplying an agent for
photodynamic therapy). The means for supplying an agent for
photodynamic therapy comprises, for example, a means for pooling
the agent for photodynamic therapy, a means for delivering the
agent for photodynamic therapy to a target site, and a means for
administering the agent for photodynamic therapy to the target
site. Thus, administration of the agent for photodynamic therapy
leads the agent for photodynamic therapy to be present at the
target site, and the irradiation the target site with a light beam
can damage the abnormal electrical conduction site or site at which
hyperexcitability occurs by necrosis or the like.
[0093] Doses of the agent for photodynamic therapy are not limited.
For example, several .mu.l to several ml, and preferably 1 ml to 10
ml of the agent for photodynamic therapy adjusted to several
.mu.g/ml to several mg/ml, and preferably 10 mg/ml to 100 mg/ml is
administered by intravenous injection. The dose per body weight is
0.1 mg/kg to 10 mg/kg, and preferably 0.5 mg/kg to 5 mg/kg.
Further, the agent for photodynamic therapy may be directly
administered to the target site by injection or other means.
[0094] Light beam irradiation can be initiated immediately or
shortly after administration of an agent for photodynamic therapy.
For example, the agent for photodynamic therapy is uniformly
distributed at a treatment site within 0.5 to 10 hours after
administration, preferably within 0.5 to 6 hours after
administration, more preferably within 0.5 to 5 hours after
administration, and further preferably within 0.5 to 3 hours after
administration, and light beam irradiation can then be initiated.
At such time, whether an agent for photodynamic therapy suitable
for treatment has accumulated at the treatment site can be
determined using the concentration of the agent for photodynamic
therapy in the blood as an indicator. When a dose of 1 mg/kg is
administered to a human, for example, treatment may be carried out
by irradiation with a light beam when the concentration is 5
.mu.g/ml to 50 .mu.g/ml, preferably 10 .mu.g/ml to 30 .mu.g/ml, and
more preferably 15 .mu.g/ml to 25 .mu.g/ml in the blood plasma.
According to the present invention, photodynamic ablation therapy
via photodynamic therapy can be initiated shortly after
administration of the agent for photodynamic therapy.
[0095] When photodynamic ablation therapy via photodynamic therapy
is performed on a human, the dose of the agent for photodynamic
therapy and the duration from administration of the agent for
photodynamic therapy to light beam irradiation can be determined
based on conditions determined using animals such as swine, rats,
or mice.
[0096] In photodynamic therapy comprising administration of an
agent for photodynamic therapy and light beam irradiation, cells
are damaged by active oxygen. In photodynamic therapy, heat is not
generated, and localized treatment is enabled. Accordingly, heat
denaturation of proteins does not occur, a target site and tissues
surrounding the target site are not necrotized, and a target site
can be selectively and assuredly damaged. When only a light beam
such as a laser beam is used without the use of an agent for
photodynamic therapy, heat can be generated at a site irradiated
with a laser beam. Accordingly, surrounding tissues can also be
damaged. Thus, the method and the apparatus using photodynamic
therapy of the present invention also have excellent effects,
compared with a method or an apparatus involving irradiation with a
laser alone without the use of an agent for photodynamic
therapy.
[0097] Types of light beams applied for treatment using the
apparatus of the present invention are not limited, and continuous
light rays can be used. A wavelength to be irradiated is 600 nm to
800 nm, and a light beam with a wavelength close to the absorption
wavelength of an agent for photodynamic therapy to be used can be
employed.
[0098] Light beams used in the apparatus of the present invention
are preferably a continuous laser beam and a semiconductor laser
beam. Light emitted from a light emitting diode (LED) light source
can also be used (LED light).
[0099] When talaporfin sodium is used as an agent for photodynamic
therapy, a semiconductor laser beam with a wavelength of 650 nm to
690 nm, preferably with a wavelength of 660 nm to 680 nm, and more
preferably with a wavelength of 664 nm.+-.2 nm is used. When an LED
light-emitting source is used, a red LED with a wavelength of
approximately 660 nm is preferable.
[0100] The intensity of the light beam to be used for the
irradiation refers to the peak intensity, and the relevant unit is
W/cm.sup.2. When photodynamic therapy is performed with light beam
irradiation, the total energy density (irradiation dose,
J/cm.sup.2) also determines the success or failure of the
photodynamic therapy, and the intensity or the total energy density
can be suitably determined in accordance with the size of the
abnormal area to be treated and other conditions. As the intensity
of a light beam to be used for the irradiation, ranges of high
intensity and low intensity are not limited, and such ranges can be
suitably determined in accordance with the type of light beam, the
depth of the abnormal site to be treated, and other conditions. For
example, the intensity of a light beam can be 1 mW/cm.sup.2 to 100
W/cm.sup.2, preferably 1 W/cm.sup.2 to 50 W/cm.sup.2, and more
preferably 2 W/cm.sup.2 to 30 W/cm.sup.2. The duration of
irradiation is 10 to 1,000 seconds, preferably 50 to 500 seconds,
and more preferably 50 to 200 seconds. Examples of the total energy
density on the surface of the site irradiated with the light beam
include 1 to 10,000 J/cm.sup.2, preferably 10 to 2,000 J/cm.sup.2,
more preferably 50 to 2,000 J/cm.sup.2, and still more preferably
100 to 1,000 J/cm.sup.2. When blood in cardiac muscle tissue is
replaced with a liquid containing artificial erythrocytes, the
light absorption coefficient can be reduced. In such a case, 10 to
500 J/cm.sup.2 is preferable.
[0101] Cardiac muscle tissue in a site to a depth of 3 mm to 5 mm
from a position irradiated with light can be a target of
photodynamic ablation.
[0102] When photodynamic ablation therapy is performed on humans,
the conditions for light beam irradiation can be determined based
on the conditions determined using animals such as swine, rats, and
mice.
[0103] In a method of necrotizing a target site with heat, tissues
surrounding the target site can also be damaged due to heat
conduction. In contrast, the method or catheter of the present
invention does not involve the use of heat that can be conducted,
but rather it involves the use of a light beam with a reachable
region that can be controlled. This enables local treatment. For
example, local treatment can be performed without damaging
surrounding normal tissues, even when a region at an abnormal
electrical conduction site or site at which hyperexcitability
occurs in the cardiac muscle is small. In therapy using the method
or catheter of the present invention, temperature increase in a
target site following light beam irradiation is within 20.degree.
C., preferably within 10.degree. C., and more preferably within
5.degree. C., and the maximum temperature is 60.degree. C. or
lower, preferably 50.degree. C. or lower, and more preferably
45.degree. C. or lower.
[0104] When a light beam is emitted, it is partially absorbed by a
catheter end, and temperature at a region close to a distal end of
the catheter can increase. Since the catheter of the present
invention involves the use of a material with a high degree of
light beam reflectivity inside itself, temperature increase at a
region close to a distal end of the catheter can be regulated
within 10.degree. C. in a blood vessel. Thus, tissue would not be
damaged by temperature increase.
Apparatus Comprising the Catheter of the Present Invention
[0105] The present invention includes an apparatus for blocking
abnormal electrical conduction in the cardiac muscle, an apparatus
for treating arrhythmia, or an apparatus for treating atrial
fibrillation using photodynamic therapy, which comprises the
catheter that performs photodynamic ablation of cardiac muscle
tissue via photochemical reactions of the present invention. Such
apparatus comprises at least a light transmission means, a catheter
comprising a light-emitting window and at least two electrodes for
potential measurement in the periphery of the window, and a light
beam generation means (i.e., a light beam generator). The catheter
may further comprise a conducting electrode and a single or a
plurality of electrodes for potential measurement at sites other
than those in the periphery of the light beam-emitting window. In
addition, the apparatus of the present invention may be equipped
with a potential measuring instrument connected to the electrode
for potential measurement through a lead wire and a power source
connected to the conducting electrode through a lead wire. An
example of the apparatus is shown in FIG. 9. A light beam generated
by the light beam generator 10 reaches a distal end of the catheter
1 through the optical fiber 4, and it is emitted from the
light-emitting window 2. The electrodes for potential measurement
that measure potential in the vicinity of the site irradiated with
light with the two electrodes 3 for potential measurement are
connected to the potential measuring instrument 11 through lead
wires. In addition to the means described above, the apparatus of
the present invention may comprise a means capable of monitoring
the amount of the agent for photodynamic therapy accumulated at the
abnormal electrical conduction site or site at which
hyperexcitability occurs and the oxygen concentration at the
abnormal site for determination of conditions for light beam
application. The apparatus may further comprise a means for
supplying the agent for photodynamic therapy to the abnormal
electrical conduction site or site at which hyperexcitability
occurs. Since the apparatus of the present invention does not have
a balloon but rather has only a diffusion fiber or a bare fiber, a
narrow site or a complex site that cannot be treated with an
apparatus having a balloon can be treated.
[0106] A light beam generation means can be the light beam
generator capable of a generating a light beam mentioned above.
[0107] A beam splitter, a filter, and the like may be suitably
provided between the light beam generator and the optical fiber or
in the middle of the optical fiber in order to transmit information
to a monitor apparatus or the like that can be included in the
apparatus.
[0108] The light-emitting window 2 emits a light beam to the
abnormal electrical conduction site or site at which
hyperexcitability occurs, the abnormal electrical conduction site
or site at which hyperexcitability occurs is irradiated with a
light beam transmitted inside the optical fiber 4, and cells at
such site are necrotized. When a tissue in the vicinity of the
junction between the pulmonary vein and the left atrium is targeted
for the treatment of atrial fibrillation, for example, cells are
preferably killed over the whole circumference. That is, the
surrounding area of the pulmonary vein is continuously irradiated
with a light beam in a linear manner. To this end, the catheter end
may be moved in a linear manner while emitting a light beam. The
range of the area of the abnormal electrical conduction site or
site at which hyperexcitability occurs irradiated with a light beam
emitted from an area close to the distal end of the optical fiber 4
is preferably from 0.5 cm.sup.2 to 3 cm.sup.2. Even when the range
of light irradiation is restricted and narrow, the direction of
irradiation can be changed by rotating the catheter 1 or the like
depending on the size of the abnormal electrical conduction site or
site at which hyperexcitability occurs, and such site can be
subjected to light beam irradiation more than once. Thus, a target
tissue can be completely destroyed. When the irradiation with a
light beam is carried out, cells at a deep site can be necrotized
by applying a high-intensity light beam or a low-intensity light
beam for a long period of time. The apparatus comprising the
catheter of the present invention has transmurality. The term
"transmurality" used herein means that the atrial muscle can be
treated from the inside to the outside. The distance from the
inside to the outside of the atrial muscle is approximately 3 mm to
5 mm. In the case of treatment of atrial fibrillation, for example,
it is sufficient to necrotize the abnormal electrical conduction
site or site at which hyperexcitability occurs to a depth of 3 mm
to 5 mm.
[0109] The means that enables monitoring of the concentrations of
an agent for photodynamic therapy and oxygen at the abnormal
electrical conduction site or site at which hyperexcitability
occurs is an apparatus that monitors fluorescence derived from the
agent for photodynamic therapy, phosphorescence, or fluorescence
derived from oxygen at the abnormal electrical conduction site or
site at which hyperexcitability occurs. Such fluorescence or
phosphorescence is transmitted back in the optical transmission
fiber. In this case, a fiber that has transmitted a laser beam may
be used as the fiber for monitoring fluorescence or
phosphorescence, or a fiber exclusively used for monitoring may be
separately provided in the catheter 1. When a fiber for monitoring
fluorescence or phosphorescence is also used as a fiber for
transmitting a light beam, the path of fluorescence or
phosphorescence is changed by a beam splitter provided between a
light beam generator and a light beam emission site, light passes
through an appropriate filter, only light with a desired wavelength
is selected, and such light then reaches a detector. When the fiber
for monitoring fluorescence or phosphorescence is separate from the
fiber for transmitting a light beam, the fiber for monitoring
fluorescence or phosphorescence is directly connected to the
detector, and fluorescence or phosphorescence reaches the detector
through the fiber. By analyzing fluorescence or phosphorescence
with the detector, the amount of the agent for photodynamic therapy
and the oxygen concentration can be monitored. Since a porphyrin
ring of an agent for photodynamic therapy emits fluorescence when
excited, for example, the amount of an agent for photodynamic
therapy can be measured by measuring the fluorescence. Also,
phosphorescence extinction occurs depending on oxygen
concentration, and oxygen concentration can thus be measured by
measuring phosphorescence. Alternatively, an oxidation fluorescence
indicator, the fluorescence intensity of which is increased by
active oxygen, may be used, or the phenomenon of a ruthenium
complex being fixed with an optical fiber or fluorescence reactions
of a ruthenium complex disappearing depending on oxygen
concentration may be utilized. Local oxygen partial pressure can be
measured according to the description in, for example, J. M.
Vanderkooi et al., the Journal of Biological Chemistry, Vol. 262,
No. 12, Issue of April 25, pp. 5476-5482, 1987, the Chemical
Society of Japan (ed.) Experimental Chemistry Course (Spectroscopy
II), pp. 275-194, 1998, or Lichini, M. et al., Chem. Commun., 19,
pp. 1943-1944, 1999. The detector is electronically connected to
the light beam generation means, the amounts of the agent for
photodynamic therapy and oxygen accumulated are fed back by the
detection means, and such amounts can be controlled in real time by
changing the conditions for light beam irradiation, such as light
beam intensity and irradiation time, according to need.
Use of the Catheter of the Present Invention
[0110] A catheter may be inserted into the body from the femoral
artery or the upper arm artery by a conventional technique. In
general, a catheter may be inserted into the right atrium from the
femoral vein, so as to reach the left cardiac tissue in a
transseptal manner by the Brockenbrough method. Such technique can
be performed by inserting the catheter 1 into the heart or an area
in the vicinity thereof from the femoral artery, the femoral vein,
the upper arm artery, or the upper arm vein, transporting the light
beam irradiation site to the abnormal electrical conduction site or
site at which hyperexcitability occurs, and irradiating such site
with a light beam. Alternatively, open-heart surgery or
laparoscopic surgery may be performed, and the abnormal electrical
conduction site or site at which hyperexcitability occurs can be
irradiated with a light beam using the catheter of the present
invention. Methods using the catheter of the present invention in a
therapy include, for example, a step of inserting a catheter into a
vein or an artery, a step of leading the catheter to the atrium by
an appropriate operation through the vein or the artery, a step of
leading the catheter to a target region, a step of positioning the
apparatus in the target region, a step of allowing the apparatus to
emit a light beam toward the target region and release energy, and
a step of measuring potential at the target site using the
electrodes for measurement. The catheter 1 can be inserted by a
conventional method. In such a case, an appropriate guide sheath or
guide wire may be used. At such time, an agent for photodynamic
therapy is allowed to be present in an abnormal area in advance by
administering the above-mentioned water-soluble agent for
photodynamic therapy to a subject of treatment via intravenous
injection or other means. The target site can be irradiated with a
light beam, so as to damage the tissue thereof.
[0111] The abnormal site may be irradiated with a light beam
continuously in a linear or dotted manner. At such time, it is
preferable that a catheter end be bent so as to face the target
site and a light beam be emitted toward the direction in which the
catheter end faces. In the case of a lateral-light-emission
catheter, it is preferable that a light beam be emitted in the
direction in which a catheter end is bent; that is, a light beam is
emitted laterally from the inside of the catheter. When atrial
fibrillation is to be treated, it is preferable that a light beam
be continuously emitted in a linear manner to perform photodynamic
ablation by electrical pulmonary vein (PV) isolation.
[0112] After the target site of cardiac muscle tissue is irradiated
with a light beam from the light-emitting window, potential is
measured at two or more points in the periphery of the region
subjected to photodynamic ablation using at least two electrodes
for potential measurement provided in the periphery of the
light-emitting window, and potential differences between arbitrary
points are measured. Measurement of potential differences enables
the determination of whether or not new tissue cells in the region
subjected to photodynamic ablation were necrotized; that is,
whether or not photodynamic ablation was satisfactorily
performed.
[0113] The present invention is described in detail with reference
to the examples below, although the technical scope of the present
invention is not limited thereto.
Example 1: Electrical Conduction Blocking Via Early Photodynamic
Therapy Using Cardiac Muscle Tissue Extirpated From a Rat (Ex
Vivo)
[0114] The right ventricular tissue isolated from a Wistar rat was
used as a sample. Talaporfin sodium was used as a photosensitive
pigment. Talaporfin sodium was dissolved in a perfusion fluid at
4.3 .mu.g/ml. Tyrode's solutions were used as perfusion fluids (95%
CO.sub.2, 5% O.sub.2 37.degree. C.). A semiconductor laser with a
central wavelength of 670.8 nm was used as an excitation light
source, and the irradiation was carried out at 150 mW/cm.sup.2 and
3.5 J/cm.sup.2.
[0115] An experiment of electric conduction blocking in the cardiac
muscle was carried out by the following procedures.
[0116] 1. The heart was extirpated under deep anesthesia and the
right ventricular wall was excised.
[0117] 2. The excised tissue was subjected to perfusion in a
Tyrode's solution comprising talaporfin sodium dissolved therein
for 2 hours.
[0118] 3. Three bipolar electrodes were positioned in cardiac
muscle tissue. One such electrode was used for electrical
stimulation (for conductance) and the two other electrodes were
used for potential measurement (A and B).
[0119] 4. A band-like laser beam was irradiated to the region
between electrodes for potential measurement to perform
photodynamic therapy.
[0120] 5. Potentials at the electrodes for potential measurement A
and B were measured during laser irradiation.
[0121] FIG. 10 shows an ex vivo experimental system. FIG. 11 shows
the positional relationship among the electrically-stimulated site,
the electrodes for potential measurement, and the site irradiated
with light in cardiac muscle tissue extirpated from a rat.
[0122] FIG. 12(a) and FIG. 12(b) each show a waveform of
transmitted stimulus measured in regions A and B before
photodynamic therapy and 5 minutes after photodynamic therapy. The
results shown in the figures demonstrate the following. Electrical
stimulus was conducted from region A to region B before
photodynamic therapy. However, electric conductivity of cardiac
muscle tissue was lost at the site irradiated with light after
photodynamic therapy, region A was electrically isolated from
region B, and electrical signals were not measured at region B.
Example 2: Acute Experiment (Open-Heart Surgery) Using Swine:
Verification of Immediate Conduction Block
[0123] Left auricular tissue obtained from a swine (body weight:
15.4 kg) was used as a sample. Talaporfin sodium was used as a
photosensitive dye, and it was administered intravenously to the
swine at 10 mg/kg of the body weight. The duration until light
irradiation after the administration of the photosensitive dye was
30 minutes. Light irradiation was carried out using a semiconductor
laser with a central wavelength of 663 nm at a power density of 5.2
W/cm.sup.2, an energy density of 208 J/cm.sup.2, and a spot size of
7 mm .PHI..
[0124] FIG. 13 shows an experimental system using swine.
[0125] The experiment for verification of immediate conduction
block using swine was carried out in accordance with the following
procedure.
[0126] 1. A swine was subjected to open-heart surgery under deep
anesthesia and the left auricle was exposed.
[0127] 2. Three bipolar electrodes were positioned in cardiac
muscle tissue of the left auricle. One such electrode was used for
electrical stimulation (for conductance) and the two other
electrodes were used for potential measurement (A and B).
[0128] 3. Talaporfin sodium was administered intravenously at 10
mg/kg.
[0129] 4. The irradiation with a band-like laser beam was carried
out in a dotted manner between electrodes for potential measurement
30 minutes after administration to perform photodynamic
therapy.
[0130] 5. The potential of an electrode for potential measurement B
was measured during laser beam irradiation.
[0131] 6. Loss of conductivity was confirmed based on a delay in
electrical signal conductivity.
[0132] FIG. 14 shows positions of the site irradiated with light
and electrodes. In the figure, references A and B each
independently represent an electrode for potential measurement, and
S represents an electrode for stimulation (i.e., a conducting
electrode). In the figure, numeral references 1 to 7 indicate
regions irradiated with laser beams. Region 1 to region 7 were
irradiated with laser beams in such order. The length of the region
irradiated was approximately 30 mm.
[0133] FIG. 15 shows the results. The line at the top indicates the
electric potential waveform at the electrode B for measurement
before light irradiation, and the other lines each indicate the
electric potential waveform at the electrode B for measurement
after light irradiation at region 1 to region 7 in the order from
top to bottom. The electric potential waveform is obtained by
measuring potential with reference to that of the counter electrode
A. Electricity conducted from the electrode S for stimulation is
transmitted, and it can be measured as a change in the electric
potential waveform at electrode B. Prior to laser beam irradiation,
cardiac muscle tissue between the electrode S for stimulation and
the electrode B for measurement is not necrotized by photodynamic
ablation, and electricity is conducted linearly from the electrode
S for stimulation to the electrode B for measurement. Once cardiac
muscle tissue between the electrode S for stimulation and the
electrode B for measurement is necrotized by photodynamic ablation
conducted via laser beam irradiation, however, electricity is not
conducted in the necrotized region. As the area of the necrotized
region increases, accordingly, delay is observed in electric
conduction at the electrode B for measurement more frequently since
electricity is conducted while bypassing the outside of the
necrotized region. As shown in the figure, electric conduction was
delayed by approximately 35.5 ms due to the formation of a light
irradiation line of approximately 30 mm before laser beam
irradiation. Thus, the acute disappearance of electric conductivity
by photodynamic therapy was verified.
INDUSTRIAL APPLICABILITY
[0134] The catheter of the present invention can be used for the
treatment of arrhythmia such as atrial fibrillation.
DESCRIPTION OF NUMERAL REFERENCES
[0135] 1: Catheter [0136] 2: Light-emitting window [0137] 3:
Electrode [0138] 4: Optical fiber [0139] 5: Mirror [0140] 6a: Prism
[0141] 6b: GRIN lens [0142] 7: Marker for monitoring direction of
light emission [0143] 8: Laser beam [0144] 9: Catheter apparatus
[0145] 10: Laser beam generating apparatus [0146] 11: Potential
measuring instrument [0147] 12: Electrode for potential measurement
[0148] 13 Electrode for stimulation (conducting electrode) [0149]
14 Amplifier [0150] 15 Oscilloscope [0151] 16 Stimulator [0152] 17
Cardiac muscle tissue [0153] 18: Signal recorder [0154] 19:
Computer
[0155] All publications, patents, and patent applications cited
herein are incorporated herein by reference in their entirety.
* * * * *